Nucleoside analogs have long been used as antimetabolites for treatment of cancers and viral infections. After entry into the cell, many nucleoside analogs are phosphorylated by nucleoside salvage pathways in a conversion to the corresponding monophosphate by nucleoside kinases, and the monophosphates are subsequently phosphorylated by a kinase to the di-, and triphosphates. Once a nucleoside analog is converted to its triphosphate inside the cell, it can serve as a substrate of DNA or RNA polymerases and can be incorporated into DNA or RNA. Incorporation of certain unnatural nucleoside analogs into nucleic acid replicates or transcripts can interrupt gene expression by early chain termination or loss of function of the modified nucleic acids. In addition, certain nucleoside analogs are very potent inhibitors of DNA and RNA polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated.
Moreover, nucleoside analogs can also interfere with a cell in a way other then DNA and/or RNA synthesis. For example, some nucleoside analogs may induce apoptosis of cancer cells, or inhibit certain enzymes other than polymerases. In yet further alternative biological effects, some nucleoside analogs are known to modulate the immune system. Typical examples for biological effects of nucleoside analogs include thymidylate synthase inhibition by 5-fluorouridine, or adenosine deaminase inhibition by 2-chloroadenosine. Further examples include inhibition of S-adenosylhomocysteine hydrolasene by planocin A.
Unfortunately, however, most of the known nucleoside analogs that inhibit tumor growth or viral infections also imply a threat to the normal mammalian cells, primarily because such analogs lack adequate selectivity between normal cells and viral or tumor cells. Therefore, there is still a need to provide methods and compositions for nucleoside analogs with improved specificity and reduced toxicity.